Intensive insulin therapy for diabetes involves providing a basal insulin, ideally present at a uniform level in the blood over a 24 hour period and a bolus or meal time (prandial) insulin to cover the added carbohydrate load from digestion concomitant with each meal.
In 1936, Hans Christian Hagedorn and B. Norman Jensen discovered that the effects of injected insulin could be prolonged by the addition of protamine obtained from the “milt” or semen of river trout. The insulin was added to the protamine and the solution was brought to pH 7 for injection. In 1946, Nordisk Company was able to form crystals of protamine and insulin and marketed it in 1950 as NPH, (Neutral Protamine Hagedorn, “NPH”) insulin. NPH insulin has the advantage that it can be mixed with an insulin that has a faster onset to compliment its longer lasting action. Eventually all animal insulins were replaced by human recombinant insulin.
Until very recently, and in many places today, basal insulin is usually provided by the administration of two daily doses of NPH insulin, separated by 12 hours. A patient eating three meals a day and using NPH insulin as the basal insulin requires five injections per day, one with each of three meals and two NPH insulin injections, one in the morning and the other at bedtime. To reduce the number of injections the patient must take, the morning dose of NPH insulin has been combined with a short acting insulin (recombinant human insulin) or a rapid acting insulin analog, such as lispro, A typical combination is a 70% NPH to 30% rapid acting insulin analog mixture. As a result, the patient can reduce the number of injections from five per day to four per day. See, e.g., Garber, Drugs 66(1):31-49 (2006).
Insulin glargine, which is currently sold under the trade name LANTUS® (Sanofi-Aventis Deutschland GmbH), is marketed as a “long-acting” insulin analog. LANTUS® can have up to 24 hour duration. LANTUS® typically starts to lower blood glucose about one hour after injection. J. Rosenstock and colleagues found that patients who took insulin glargine had a much lower risk of low blood glucose (hypoglycemia) than the patients who took NPH insulin. While LANTUS® is designed to cover the average patient's basal insulin needs over a 24 hour time period, the reality is that for many patients, it does not last long enough, causing them to be hyperglycemic, typically in the early morning hours. For some patients, LANTUS® is effective for only 12 hours, for others it is effective for 18 hours, and for still others it is effective for 24 hours. In an attempt to make LANTUS® last for 24 hours, the dose of LANTUS® is frequently increased. Unfortunately in these cases the risk of nocturnal hypoglycemia is also increased, which is a serious life-threatening condition that can lead to death.
Glargine cannot be mixed with other short or rapid acting insulins because the mixture causes glargine to precipitate prior to injection and administration of a precipitated insulin makes it virtually impossible to administer a known and reliable dose. The manufacturer of glargine warns users against mixing glargine with any other insulin.
It is therefore an object of the present invention to provide insulin formulations that can be used to reduce the number of daily injections to three.
It is another object of the present invention to provide a basal-bolus insulin formulation.
It is still another object of the present invention to provide a stable insulin formulation having immediate and long term release characteristics.